This invention relates to novel prodrugs and, more particularly, to phosphorylated derivatives of glycosidase inhibitors.
It is known that polyhydroxylated pyrrolidines and piperidines provide an extensive class of powerful and specific glycosidase inhibitors. See, for example, Scofield et al., Life Sci. 39, 645-650 (1986); Elbein, Ann. Rev. Biochem. 56, 497-534 (1987); and Fleet et al., FEBS Lett. 237, 128-132 (1988). Several of these glycosidase inhibitors have been found to inhibit human immunodeficiency virus (HIV) syncytium formation and virus replication, thereby indicating their potential use as antiretroviral agents. Three such compounds thus suggested as potential anti-AIDS drugs are castanospermine, 1-deoxynojirimycin (DNJ) and 2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP). See, for example, Sunkara et al., Biochem. Biophys. Res. Commun. 148(1), 206-210 (1987); Tyms et al., Lancet, Oct. 31, 1987, pp. 1025-1026; Walker et al., Proc. Natl. Acad. Sci. USA 84, 8120-8124 (1987); and Gruters et al., Nature 330, 74-77 (1987). N-alkylated derivatives of these compounds also have been suggested as potential antiviral agents and, in particular, the n-butyl derivative of 1,5-dideoxy-1,5-imino-D-glucitol, also referred to as N-butyl-deoxy-nojirimycin, has been shown to reduce the virus titer by an order of greater than five logarithms at noncytotoxic concentrations by Karpas et al., Proc. Natl. Acad. Sci. USA 85, 9229-9233 (1988). See, also copending application Ser. No. 07/288,528, filed Dec. 22, 1988, and U.S. Pat. No. 4,849,430.
Some of the glycosidase inhibitors which are potent inhibitors of .alpha.-glucosidases, particularly disaccharidases, are suggested as useful agents for treatment of hyperglycemia, hyperlipoproteinaemia, and various gastrointestinal problems. See, e.g., U.S. Pat. Nos. 4,065,562; 4,182,767; 4,278,683; 4,533,668; and 4,639,436.
A problem that arises in the oral administration of the glycosidase inhibitors for therapeutic use is that the concomitant inhibition of the enzymatic splitting of dietary disaccharides can cause undesirable gastrointestinal problems such as diarrhea, digestive flatulance and the like. A means of overcoming these problems without loss of the desired therapeutic benefit of the drug would have significant use.